IRAK-4 is a member of the IRAK family which is a protein kinase, and lies downstream of all Toll-like receptors (TLRs) excluding TLR3 and interleukin-1, -18 and -33 receptors (IL-1R, IL-18R, IL-33R) (Non-Patent Document 1). IRAK-4 is activated via an adapter molecule which is called myeloid differentiation factor 88 (MyD88), and transmits signals in downstream. The signaling via MyD88 activates downstream molecule including NF-κB and MAPK, and produces cytokine, chemokine and the like which are involved in inflammatory response (Non-Patent Document 2).
Accordingly, IRAK-4 and MyD88 are considered to contribute to physiological reactions such as protection against pathogen, inflammation, control of natural immunity and/or acquired immunity, and cell survival and/or growth, by controlling the production of an inflammatory mediator. In addition, they are involved in acute and chronic inflammatory diseases, and autoimmune diseases such as rheumatoid arthritis (Non-Patent Document 3), systemic lupus erythematosus (Non-Patent Document 4), multiple sclerosis (Non-Patent Document 5) and the like (Non-Patent Document 6).
In addition, since the signaling via IRAK-4 and MyD88 is involved in NF-κB and MAPK, it is also be intimately related to cell growth. For example, it is evident that therapeutic effect of vinblastine on malignant melanoma is increased due to inhibition of IRAK-4 and IRAK-1 (Non-Patent Document 7).
From the foregoing, IRAK-4 inhibitor has the potential to show high efficacy of the treatment of acute and chronic inflammatory disease, autoimmune disease and cancer.
Examples of the compound having a structure similar to the compound described in the present specification include the following compounds.
(1) A compound represented by the following formula:
wherein    Ring A is monocyclic heteroaryl;    R1 is optionally substituted monocyclic or bicyclic heteroaryl;    R2 is —CONH2, —CONH—R0, —CONH—R00—OH, phenyl, oxadiazolyl, tetrazolyl or the like;    R3 is H, hetero cycloalkyl (optionally substituted by R0, halogen and the like) or the like;    R0 is lower alkyl; and    R00 is lower alkylene,    which is IRAK-4 inhibitor and useful for the prophylaxis or treatment of inflammatory disease, autoimmune disease and the like (Patent Document 1).